Recent studies have shown a role for the V1/V2 domain of the HIV-1 ENV protein as a target in HIV-1 vaccines. A series of potent and broadly neutralizing monoclonal antibodies (MAbs) targeting a class of quaternary epitopes that were dependent on several positions in the V2 region were isolated in one study (Walker et al., 2009, Science 326:285-289; Moore et al., 2011, Journal of Virology 85:3128-3141). These antibodies react preferentially with native trimeric Env complexes. Further studies have shown that a small conserved sequence in the V2 domain interacted with α4β7 integrin, the mucosal homing receptor for activated T cells, and that this interaction strongly enhanced infection of those cells (Nawaz et al., 2011, PLoS Pathog 7:e1001301; Cicala et al., 2009, Proc Natl Acad Sci USA 106:20877-20882). A third finding came from the analysis of correlates of protection in the recently concluded RV144 vaccine trial conducted in Thailand, the first HIV vaccine trial that resulted in some protection against infection (Rerks-Ngarm et al., 2009, N Engl J Med 361:2209-2220). Protection in this trial was shown to correlate with an increased titer of antibodies that bound to a V1/V2 fusion protein, but not to any other factor analyzed, including avidity and titers of Env-specific IgG and IgA, viral neutralizing activity or levels of Env-specific CD4+ T cells (Haynes et al., 2012, The New England Journal of Medicine 366:1275-1286).